Angiotensin II (Ang II) has a critical role in tissue destruction in a variety of chronic conditions. Ang II antagonism has become a dominant therapeutic intervention in a number of cardiovascular, renal and hypertensive disorders that has unexpectedly revealed benefit in atherosclerosis. Atherosclerosis is characterized by some of the same processes that destroy other tissues, however, its pathophysiology is unique in its absolute dependence on lipid deposition within the vessel wall. Thus, although the acute sequelae of atherosclerosis occur later in life, the lipid deposition begins in utero and vascular remodeling proceeds throughout childhood. This underscores that further understanding of atherogenesis can lead to preventive measures that can begin in childhood. The PI's preliminary data suggest that non-hypertensive dose of Ang II promotes initiation of atherosclerotic lesion without affecting the lipid profile. Clinical and animal studies suggest that Ang II affects local vascular accumulation of lipids, although the precise mechanisms are not understood. Monocyte infiltration and uptake of lipid constitute the hallmark of atherosclerosis, namely, formation of macrophage foam cells. Macrophages have recently been revealed to have a crucial role in atherosclerosis. Thus, macrophages can provide sufficient lipid acceptors to correct hyperlipidemia and prevent atherosclerosis, conversely, even without affecting the plasma lipid profile, perturbations in macrophage lipid metabolisms, especially lipid efflux, promotes atherosclerosis. How Ang II relates to macrophage function is not well known. The PI's preliminary data indicate that Ang II regulates macrophage accumulation following injury; that macrophages are a source of Ang II; that Ang II promotes development of atherosclerotic lesions; that macrophages in the atherosclerotic lesion express AT1 receptor; and that macrophages deficient in AT1 receptor have more lipid efflux. These observations form the basis for these projects, which is to define the role of Ang II within the vessel walls and within macrophages in atherosclerosis. We will use chimeric mice with transplantation of genetically engineered hematopoetic stem cells into genetically engineered mice. The effects of bone marrow-or vessel-deficiency in Ang II on atherosclerosis will be assessed in vivo. In addition, in vitro macrophage studies will examine the role of Ang II in atherogenic processes including macrophage lipid handling, migration and apoptosis.